This project is directly concerned with the learning and motivational processes that mediate ethanol-seeking behavior. Our long-term goal is to improve our understanding of the behavioral and neurobiological processes that contribute to the etiology, maintenance, elimination and relapse of alcoholism. The general experimental strategy involves study of ethanol's motivational effects in animals (mice) using the place conditioning procedure. Special emphasis will be placed on the learning that results from the predictive relationship between environmental stimuli and exposure to ethanol's rewarding or aversive effects. Our central organizing hypothesis is that ethanol-predictive stimuli are critical for motivating, directing and reinforcing ethanol-seeking behavior, including the phenomenon of relapse after a period of abstinence or after extinction. Aim 1 will address environmental influences and gene x environment interactions. Proposed studies will examine the effects of stimulus modality (visual, tactile, olfactory, spatial), compound cue interactions, sign tracking, genotype, and drug type. Aim 2 will address post-conditioning manipulations, with an emphasis on those producing extinction and relapse to ethanol seeking. Proposed studies will examine parametric determinants of extinction (e.g., trial number, duration and spacing) and manipulations hypothesized to affect rate of extinction or sensitivity to recovery of conditioned preference (e.g., prior expression of place preference, pretreatment with the opioid antagonist naloxone, exposure to non-extinguished conditioned stimuli). Finally, Aim 3 will extend studies initiated during the current project period to identify and characterize the neurobiological mechanisms underlying ethanol-induced conditioned place preference. Proposed studies will examine specific brain areas and neurotransmitter systems thought to be involved in either the acquisition or the expression of conditioned place preference using both tactile and visual-spatial cues. Brain areas of interest include: ventral tegmental area, amygdala, nucleus accumbens, bed nucleus of the stria terminalis, anterior cingulate cortex and the CA1 region of hippocampus. Neurotransmitters of interest include: dopamine, gamma-aminobutyric acid, glutamate, serotonin, and opioid peptides. In addition to improving our understanding of the roles played by ethanol-predictive stimuli, these studies will elucidate the brain mechanisms that underlie behavior controlled by ethanol-paired stimuli. This project should help focus future research on the neurobiological mechanisms of ethanol-seeking behavior, aid in the development of beneficial treatments for alcohol related disorders, and facilitate identification of more effective relapse prevention strategies. These studies could prove to be especially useful in the future evaluation of putative pharmacotherapies to reduce craving and in the design of behavioral interventions (e.g., cue-exposure therapy) to decrease ethanol-seeking behavior. PUBLIC HEALTH RELEVANCE Our long-term goal is to improve our understanding of the behavioral determinants and brain mechanisms that underlie ethanol-seeking behavior in human alcoholics. This project focuses on basic learning processes related to ethanol's primary and conditioned rewarding and aversive effects, which are believed to be critically involved in the etiology, maintenance, elimination and relapse to alcoholism in humans. These studies could prove to be especially useful in the future evaluation of putative pharmacotherapies to reduce craving and in the design of behavioral interventions (e.g., cue-exposure therapy) to decrease ethanol-seeking behavior.